Specific ablation of Stat3β distorts the pattern of Stat3-responsive gene expression and impairs recovery from endotoxic shock
Open accessAbstract
Alternative splicing of the gene for Stat3, a transcription factor activated by the IL-6 family of cytokines, produces two isoforms: Stat3alpha and a dominant-negative variant, Stat3beta. Stat3beta-deficient mice were generated by gene targeting. Despite intact expression and phosphorylation of Stat3alpha, overall Stat3 activity was impaired in Stat3beta(-/-) cells. Global comparison of transcription in Stat3beta(+/+) and Stat3beta(-/-) cells revealed stable differences. Stat3beta-deficient mice exhibit diminished recovery from endotoxic shock and hyperresponsiveness of a subset of endotoxin-inducible genes in liver. The hepatic response to endotoxin in wild-type mice is accompanied by a transient increase in the ratio of Stat3beta to Stat3alpha. These findings indicate a critical role for Stat3beta in the control of systemic inflammation.
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Direct side-by-side comparisons of STAT3α phosphorylation in Stat3β−/−, Stat3β+/− or Stat3β+/+ cells were not presented in those studies, and the loss of STAT3 DNA binding or STAT3 reporter gene activity appeared to be greater than could be anticipated based solely on the ratios of STAT3α/STAT3β in WT cells.
“However, direct side-by-side comparisons of STAT3α phosphorylation in Stat3β−/−, Stat3β+/− or Stat3β+/+ cells were not presented in those studies and the loss of STAT3 DNA binding or STAT3 reporter gene activity appeared to be greater than could be anticipated based solely on the ratios of STAT3α/STAT3β in WT cells [16].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [16]
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Experimental — accuracy not yet measuredIn vivo studies indicate a requirement for STAT3β during endotoxic assault, a requirement for STAT3α in IL-8 synthesis, and differential roles for STAT3α and STAT3β in anti-inflammatory responses.
“spliceform-specific functions have been indicated by various in vivo studies showing a requirement for STAT3β during endotoxic assault [16], but a requirement for STAT3α in IL-8 synthesis [17], as well as differential roles for STAT3α and STAT3β in anti-inflammatory responses [15].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [16]
Others have concluded that there were no noticeable changes in STAT3α regulation in the absence of STAT3β (i.e. in Stat3β−/− MEFs) following cytokine stimulation.
“Indeed, others have also concluded that there were no noticeable changes in STAT3α regulation in the absence of STAT3β (i.e. in Stat3β−/− MEFs) following cytokine stimulation [16].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [16]
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Acute-Phase Proteins and Other Systemic Responses to Inflammation
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Principles of interleukin (IL)-6-type cytokine signalling and its regulation
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- Authors
- Yoo, J.-Y., Huso, D. L., Nathans, D., & Desiderio, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Desiderio, Stephen
- ORCID
- Yoo, Joo-Yeon
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2002-02
- Volume
- 108
- Issue
- 3
- Pages
- 331-344
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2032260589
- Cited by
- 139
- References
- 4
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 2 · 2014: 9 · 2013: 4 · 2012: 7
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 4184 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Massachusetts Institute of Technology
- Johns Hopkins University
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- STAT3β, alternative splicing, dominant-negative isoform, endotoxic shock, endotoxin, systemic inflammation, hepatic gene expression, liver, IL-6 family cytokines, transcriptional regulation, gene targeting
- MeSH terms
- Acute-Phase Proteins, Amino Acid Sequence, Animals, Base Sequence, DNA-Binding Proteins, Endotoxins, Liver, Molecular Sequence Data, Shock, Septic, Transcriptional Activation, Trans-Activators, Alternative Splicing, Mice, Knockout, Protein Isoforms, STAT3 Transcription Factor, Mice
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